FDA Rejects Novo Nordisk's Insulin Degludec

Miriam E. Tucker

February 11, 2013

The US Food and Drug Administration (FDA) has declined to approve Novo Nordisk's insulin degludec, issuing instead a "complete response letter" in which it requests additional cardiovascular-outcomes data from a dedicated trial.

In a statement, the company says it is evaluating the content of the complete response letter and will work closely with the FDA to provide the requested data, which it does not anticipate being able to do in 2013.

Mike Rulis, a spokesperson for Novo Nordisk, told Medscape Medical News: "This is all the detail we can give at this point. We hope to have a meeting with the FDA, sooner rather than later, to discuss this further."

In November 2012, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 8 to 4 in favor of licensing degludec for people with both type 1 and type 2 diabetes but had stipulated that the company conduct a rigorous postmarketing study to evaluate cardiovascular safety.

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Insulin degludec is a long-acting basal insulin that forms soluble multihexamers on subcutaneous injection. It has a half-life twice as long as currently available basal insulin products, with a 42-hour duration of effect.

Much of the discussion at the November hearing surrounded an evident signal of an increased risk for major adverse cardiovascular (CV) events (MACE). Injectable insulin products are exempted from the 2008 FDA guidance requiring that manufacturers of new diabetes therapies conduct trials specifically designed to assess CV risk. However, the FDA still asks companies to prospectively collect CV data in their phase 2/3 clinical trials.

Novo Nordisk had provided an analysis at the hearing showing that there was no statistically increased risk for MACE, but some of the FDA's analyses, using different criteria, demonstrated hazard ratios for an increased risk.

Advisory committee members agreed that the absolute number of MACE was too small to conclusively determine whether the signal was real. The majority, however, agreed with the company that any study to examine this could be done on a postmarketing basis.

The FDA usually follows the recommendation of its advisory panels.

The US decision not to approve insulin degludec contrasts with that of the European Union, which licensed the product in 2 forms, known as Tresiba (insulin degludec) and Ryzodeg (insulin degludec/insulin aspart combination) just last month; they are also approved in Japan and Mexico.